Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Aug 18:12:975644.
doi: 10.3389/fonc.2022.975644. eCollection 2022.

Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer

Francesco Melia  1 , Palita Udomjarumanee  2 , Dmitry Zinovkin  3 , Nahid Arghiani  1   4 , Md Zahidul Islam Pranjol  1
Affiliations
Review

Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer

Francesco Melia et al. Front Oncol. .

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The disease still remains incurable and highly lethal in the advanced stage, representing a global health concern. Therefore, it is essential to understand the causes and risk factors leading to its development. Because age-related cellular senescence and type 2 diabetes (T2D) have been recognised as risk factors for CRC development, the recent finding that type 2 diabetic patients present an elevated circulating volume of senescent cells raises the question whether type 2 diabetes facilitates the process of CRC tumorigenesis by inducing premature cell senescence. In this review, we will discuss the mechanisms according to which T2D induces cellular senescence and the role of type 2 diabetes-induced cellular senescence in the pathogenesis and progression of colorectal cancer. Lastly, we will explore the current therapeutic approaches and challenges in targeting senescence.

Keywords: colon cancer; diabetes; endothelial cells; fibroblast; senescence; tumour microenvironment.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Mechanism of hyperglycaemia-induced cellular senescence. (A) Hyperglycaemia induces ROS overproduction via mitochondria overload which results in oxidative stress. ROS causes DNA damage response (DDR) activation, due to DNA oxidative damage, and p38 MAPK pathway activation. DDR and p38 MAPK determines cell cycle arrest and NF-κB upregulation. NF-κB activation results in SASP secretion. ROS also generates ER stress via chemical modification of ER proteins. ER stress activates the unfolded protein response (UPR). The activation of the ATF6α branch of the UPR causes expression of SA-β-Gal and changes in cellular morphology via cytoskeletal vimentin rearrangement. (B) Hyperglycaemia increases polyol pathway activity, causing reduced antioxidant glutathione synthesis due to reduce NADPH availability. Glutathione deficiency contributes to the inability of the cell to counteract oxidative stress. (C) Hyperglycaemia causes advance glycation end products (AGEs) via glycation of intracellular and extracellular proteins. Intracellular AGEs cause ER stress which results in SA-β-Gal activity and change in cellular morphology. Extracellular ages cause AGE receptor (RAGE) activation which results in ROS production and NF-κB activation. This ultimately results in cell cycle arrest and SASP secretion. (D) Hyperglycaemia results in increased hexosamine pathway activity due to increased glucose-6-phosphate production. This pathway produces N-acetyl glucosamine (GlcNAc) which induces TGF-β expression. TGF-β activates the p38 MAPK which results in cell cycle arrest and SASP secretion. (E) PKC signalling contributes to the activation of senescence pathways. Hyperglycaemia results in increased diacyl glycerol production and activation of PKC δ isoform. PKC δ activation causes TGF-β expression and ROS production which, in turn, activate PKC δ in a positive feedback loop mechanism. In addition, ROS also activate PKC η which induces SA-β-Gal activity. Downregulation of aPKC and cPKC results in inactivation of FoxO3a which results in ROS production. Cell cycle arrest, SASP secretion, change in cellular morphology and SA-β-Gal activity are the major characteristics of senescence.
Figure 2
Figure 2
SASP activity within the tumour microenvironment. (A) Angiogenesis is stimulated by CCL23, VEGF and GDF15. CCL23 is secreted by senescent T cells, while VEGF and GDF15 are secreted by senescent fibroblasts. (B) Metastasis is promoted by GDF15 and CCL5, which are secreted by senescent fibroblasts and T cells, respectively. Senescent T cells contribute to tumorigenesis by inducing inflammation via the release of TNF-α. Metastasis is also induced in tumour cells that express the receptor CXCR3 via the SASP component CXCL11 secreted by senescent endothelial cells. However, CXCL11 also presents anti-tumorigenic activity by recruiting T cells and NK cells at the site of tumour. (C) Tumour apoptosis is induced by IL-29 secreted by senescent T cells. In addition, IL-29 contributes to cancer-specific immune response via the recruitment of NK cells. (D) Senescent tumour cells evade the immune system via the secretion of elevated CXCL12 levels, inducing CXCR4 internalisation in T cells and impairing T cell directional migration.
Figure 3
Figure 3
Potential combination therapies for colorectal cancer. After chemotherapeutic treatment, tumour cells are either killed or become senescent. CAR T cell immunotherapy or senolytic therapy can be used to avoid escape from the senescent state and tumour relapse. CAR T cell immunotherapy targets antigens present on colorectal cancer cells such as NKG2DLs, HER-2, GUCY2C and uPAR. Senolytic therapy targets the SA-β-Gal via the compound SSK1 or inhibits the mitochondrial enzyme GLS1, which is important for tumour cell metabolism.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clin (2021) 71(3):209–49. doi: 10.3322/caac.21660 - DOI - PubMed
    1. UK CR . Bowel cancer statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/s....
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: A Cancer J Clin (2018) 68(1):7–30. doi: 10.3322/caac.21442 - DOI - PubMed
    1. Brenner H, Hoffmeister M, Stegmaier C, Brenner G, Altenhofen L, Haug U. Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840 149 screening colonoscopies. Gut (2007) 56(11):1585–9. doi: 10.1136/gut.2007.122739 - DOI - PMC - PubMed
    1. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. . Colorectal cancer statistics, 2020. CA: A Cancer J Clin (2020) 70(3):145–64. doi: 10.3322/caac.21601 - DOI - PubMed

LinkOut - more resources